Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is an enzyme which forms an reactive oxygen species (to be referred to as ROS) by receiving an electron from NADPH and finally delivering it to an oxygen molecule. Physiologically, the aforementioned enzyme mainly existing in phagocytes is taking an important role in a defense system in a living body against invasion of foreign bodies such as microorganisms, which is sterilization of them by forming ROS and the like. However, it is known that excess formation of ROS by the enzyme causes digestion of protein and DNA and the damage to membranes by lipid peroxide and thereby becomes the cause of disorders of cells and tissues and furthermore of various diseases including inflammatory diseases, vascular diseases, neurodegenerative diseases, cancers, heart diseases and the like (cf. non-patent reference 1 and non-patent reference 2). However, since expression of the NADPH oxidase which forms ROS is systemically distributed, there is a possibility of causing side effects when this is considered as a target of drug discovery.
On the other hand, an NADPH oxidase family, NOX1, distributing in non-phagocytic cells has been identified by the recent studies, and it has been reported that ROS is tissue-specifically formed in cells other than phagocyte (cf. non-patent reference 3). It has been reported that NOX1 is present in the large intestine in a large amount and causes cell proliferation and upregulation of various genes, suggesting that it is concerned in various diseases in the large intestine.
There are various reports on the amino acid sequences having high homology with NOX1 and nucleotide sequences coding for the sequences. These are registered at data bases as accession numbers AF166328 (GENPEPT), AJ438989 (GENPEPT), HSA438989 (GENBANK), AF127763 (GENPEPT), AF166327 (GENPEPT), Q9YSS8 (SWISSPROT) and Q9WV87 (SWISSPROT), and reported in the non-patent reference 4, patent reference 1 and patent reference 2. The molecules are described in these references as factors which exist and function in the large intestine and are useful for the diagnosis of large bowel cancer, development of a therapeutic agent for large bowel cancer and the like. A sequence having high homology with NOX1 is described in the patent reference 3 which describes that the sequence is concerned in the production of active oxygen and useful for the treatment of diseases related to abnormal cell growth such as cancers and prostatic hypertrophy.
RA is a chronic inflammatory disease of unknown origin, which has the mainlocus of lesion in the synovial tissue and causes flare, swelling, heat sensation, pain, movement restriction and destruction of joints. Overproduction of inflammatory cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-12 (IL-12), interleukin-15 (IL-15), interleukin-18 (IL-18), tumor necrosis factor-α (TNF-α) and the like, nitric oxide (NO), prostaglandins (PGs) and the like is known in the synovial tissue of RA (cf. non-patent reference 5). In recent years, a therapeutic method aimed at IL-1, IL-6 or TNF-α has been developed using a monoclonal antibody and a soluble receptor, and its efficacy is drawing attention (cf. non-patent reference 6). However, there is a group of patients in which complete remission cannot be introduced by the conventional therapeutic method which uses a therapeutic target molecule as the mechanism (cf. non-patent reference 7). Accordingly, identification of a new therapeutic target molecule different from the already known reports is expected.
It is known that ROS activates NFκB which is a transcription factor that expresses and induces various molecules, via oxidation-reduction control (cf. non-patent reference 8). Among the molecules of which expression is induced by NFκB, TNFα known as an inflammatory cytokine is also broadly acknowledged in the clinical field as the target of anti-RA agents (cf. non-patent reference 9), and COX-2 known as a prostaglandin synthesizing enzyme is also broadly acknowledged in the clinical field as the target of agents for treating RA and osteoarthritis (cf. non-patent reference 10).
On the other hand, standards on the classification of RA have been defined from an American university (cf. non-patent reference 11). However, since these standards are merely landmarks and disease condition patterns thereof are various, it has been considered that diagnosis of RA, particularly quantitative and convenient diagnosis thereof, is difficult to carry out. A quantitative and convenient diagnosis method for RA has been expected.
(Patent reference 1) International publication WO 02/06515 pamphlet
(Patent reference 2) International publication WO 01/96390 pamphlet
(Patent reference 3) International publication WO 00/28031 pamphlet
(Non-patent reference 1) Trends in Pharmacological Science, (USA), 2000, vol. 21, pp. 119–120
(Non-patent reference 2) Federation of European Biochemical Society, (Germany), 1991, vol. 281, pp. 9–19
(Non-patent reference 3) Nature, (England), 1999, vol. 401, pp. 79–82
(Non-patent reference 4) Science, (USA), 2000, vol. 287, p. 138
(Non-patent reference 5) The Journal of Experimental Medicine, (USA), 1991, vol. 173, pp. 569–574
(Non-patent reference 6) Current Pharmaceutical Biotechnology, (USA), 2000, vol. 1, pp. 217–233
(Non-patent reference 7) Nature Reviews Immunology, (England), 2002, vol. 2, pp. 364–371
(Non-patent reference 8) The Journal of Biological Chemistry, (USA), 1993, vol. 268, pp. 11380–11388
(Non-patent reference 9) Arthritis & Rheumatism, (USA), 1999, vol. 36, pp. 1681–1690
(Non-patent reference 10) Arthritis & Rheumatism, (USA), 1998, vol. 41, pp. 1591–1602
(Non-patent reference 11) “Medicine”, edited by J. Axford, (USA), Blackwell Science, 1996, pp. 3.18–3.22